PURPOSE To determine the effect of implementing a screening tomosynthesis program on real-world clinical performance by quantifying differences between interpretation times for conventional screening mammography and combined tomosynthesis and mammography for multiple participating radiologists with a wide range of experience in a large academic center. MATERIALS AND METHODS In this HIPAA-compliant, institutional review board-approved study, 10 radiologists prospectively read images from screening digital mammography or screening combined tomosynthesis and mammography examinations for 1-hour-long uninterrupted sessions. Images from 3665 examinations (1502 combined and 2163 digital mammography) from July 2012 to January 2013 were interpreted in at least five sessions per radiologist per modality. The number of cases reported during each session was recorded for each reader. The experience level for each radiologist was also correlated to the average number of cases reported per hour. Analysis of variance was used to assess the number of studies interpreted per hour. A linear regression model was used to evaluate correlation between breast imaging experience and time taken to interpret images from both modalities. RESULTS The mean number of studies interpreted in hour was 23.8 ± 0.55 (standard deviation) (range, 14.4-40.4) for combined tomosynthesis and mammography and 34.0 ± 0.55 (range, 20.4-54.3) for digital mammography alone. A mean of 10.2 fewer studies were interpreted per hour during combined tomosynthesis and mammography compared with digital mammography sessions (P < .0001). The mean interpretation time was 2.8 minutes ± 0.9 (range, 1.5-4.2 minutes) for combined tomosynthesis and mammography and 1.9 minutes ± 0.6 (range, 1.1-3.0) for digital mammography; interpretation time with combined tomosynthesis and mammography was 0.9 minute longer (47% longer) compared with digital mammography alone (P < .0001). With the increase in years of breast imaging experience, the overall additional time required to read images from combined tomosynthesis and mammography examinations decreased (R(2) = 0.52, P = .03). CONCLUSION Addition of tomosynthesis to mammography results in increased time to interpret images from screening examinations compared with time to interpret images from conventional digital mammography alone.